Magnetic Resonance Imaging (MRI) is a well-established and powerful technique for studying the internal structure of the human body. In the field of MRI, various lanthanide chelates of cyclen-based macrocyclic chelating agents have been proposed as contrast agents. Such macrocyclic chelating agents form particularly stable chelate complexes with the contrast-generating paramagnetic metal ions, such as gadolinium or dysprosium, and thus are suitable carriers for the metal ions to ensure appropriate biodistribution and elimination.
Cyclen (1,4,7,10-tetraazacyclododecane) is a key compound in the preparation of many of these macrocyclic chelants. The group of tri-N-alkylated cyclens constitutes another important group of compounds for the preparation of such macrocyclic chelants. DO3A (1,4,7,10-tetraazacyclododecane-N,N′,N″-triacetic acid) is one such tri-N-alkylated cyclen compound that forms basis for Magnetic Resonance (MR) contrast agents. A group of related compounds is the protected forms of the DO3A compound, such as DO3A-tri-t-butyl ester (1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid tri-t-butyl ester), wherein the three carboxyl groups are protected.
Protected DO3A compounds, such as DO3A-tri-t-butyl ester, and the salts thereof, are valuable intermediates in the preparation of MR contrast agents based on DO3A, such as e.g. Gd(HP-DO3A) (ProHance™), and Gd(DO3A-butrol) (Gadovist™).
DO3A-tri-t-butyl ester is a commercially available product, but in addition to being expensive the commercially available products contain impurities of both the di-alkylated and tetra-alkylated cyclen. Some methods for preparation of the compound are known from the prior art.
U.S. Pat. No. 5,419,893 is directed to chelating agents, such as cyclene based compounds, and the preparation thereof. A preparation of DO3A-tri-t-butyl ester from cyclen and t-butylbromo acetate is presented. The preparation includes purification by flash chromatography. The products are prepared as free bases.
WO 2005/003105 presents a method of preparing tri-alkylated 1,4,7,10-tetraazacyclododecanes by reaction of cyclen and appropriate electrophiles. The reaction takes place in an aprotic solvent such as chloroform. The product is purified by column chromatography. The products are prepared as free bases.
As noted above, DO3A-tri-t-butyl ester is an important starting material for the preparation of macrocyclic chelating agents and MR contrast agents. Commercially available DO3A-tri-t-butyl ester is expensive and comprises impurities. Existing synthetic routes require expensive and time consuming purification, such as chromatography, being a particular drawback when producing in large scale. A new process for preparation of DO3A-tri-tert-butyl ester, which is less expensive and which provides a product of improved purity is hence sought.